Abstract 372: OxLDL-Induced Apoptotic Dendritic Cells as a Novel Therapy for Atherosclerosis

Abstract

Introduction: Tolerogenic dendritic cells (DCs) have been previously described to protect against atherosclerosis. A tolerogenic phenotype in DCs can be induced by apoptotic cell clearance and these DCs can prevent inflammatory responses. In this study, we took advantage of the fact that oxidized low-density lipoprotein (oxLDL) induces apoptosis in DCs. These oxLDL-induced apoptotic DCs (apop-DCs) enabled us to deliver an atherosclerosis-specific antigen to DCs in the context of regulatory signals. Hypothesis: We hypothesized that an adoptive transfer of apop-DCs would limit immune responses and thereby reduce atherosclerosis. Methods and Results: In vitro DCs pre-exposed to apop-DCs showed significantly less pro-inflammatory cytokines IL-6 (2493±73 vs. 1500±95 pg/mL) and TNF-α (311±12 vs. 30±7 pg/mL), but significantly increased anti-inflammatory IL-10 production (12±12 vs. 106±11 pg /mL) in response to LPS, compared to control DCs. Moreover, these DCs resulted in a dramatic reduction of T cell proliferation, accompanied by an about 8-fold decrease of Th1 cells, while regulatory T cells (Tregs) were 4.5-fold increased. Adoptive transfer of apop-DCs to LDLrKO mice prior to Western-type diet resulted in tolerogenic splenic DCs and increased circulating Tregs. Moreover, we determined a decreased proliferative capacity of splenic T cells and found less adventitial T cells in the aortic root. Serum IL-10 levels were significantly increased, while TNF- levels were reduced. Interestingly, we observed a 32% decrease in monocyte numbers, with 13% less Ly-6C hi and 14% less CCR2 + monocytes, and a 48% decrease in serum CCL2 levels. This translated into significantly less lesional macrophages in the aortic root. The overall reduced inflammatory status upon apop-DC-treatment translated into a 40% reduction in aortic root lesion size. Conclusions: We are the first to show the potential of apop-DC-treatment for atherosclerosis. In the future treatment of patients with autologous oxLDL-induced apop-DCs may prove a safe and very efficient treatment of atherosclerosis and acute vascular syndromes.